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  1. Article ; Online: Carrier screening for Krabbe disease in an isolated inbred community.

    Ezer, Shlomit / Zuckerman, Shachar / Segel, Reeval / Zlotogora, Joël

    American journal of medical genetics. Part A

    2022  Volume 188, Issue 9, Page(s) 2555–2559

    Abstract: Infantile Krabbe disease (OMIM 245200) is a severe, fatal autosomal recessive neurodegenerative disorder that is relatively frequent in two Muslims villages within Jerusalem. After the characterization of the founder mutation, a population carrier ... ...

    Abstract Infantile Krabbe disease (OMIM 245200) is a severe, fatal autosomal recessive neurodegenerative disorder that is relatively frequent in two Muslims villages within Jerusalem. After the characterization of the founder mutation, a population carrier screening for Krabbe disease became a component of the Israeli program for the detection and the prevention of birth defects. Between 2010 and 2018, 3366 individuals were tested and among them 247 carriers for Krabbe disease were identified (7.3%). Most of the 21 carrier couples identified that had pregnancies after being informed that they were at risk used preventive measures including termination of pregnancies of affected fetuses. During the study period, eight children affected with Krabbe disease were born in the villages, four to couples not detected though the program. Twenty years after the beginning of the carrier screening program, Krabbe disease remained relatively frequent in the villages. The establishment of a genetic clinic in the villages may allow to improve the carrier screening program while giving individual counseling for the risk to the other genetic diseases existing in the villages.
    MeSH term(s) Child ; Female ; Genetic Carrier Screening ; Humans ; Leukodystrophy, Globoid Cell/diagnosis ; Leukodystrophy, Globoid Cell/epidemiology ; Leukodystrophy, Globoid Cell/genetics ; Mass Screening ; Pregnancy
    Language English
    Publishing date 2022-07-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.62882
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1376/A: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  2. Article ; Online: Intellectual disability syndrome associated with a homozygous founder variant in

    Birnbaum, Rivka / Ezer, Shlomit / Lotan, Nava Shaul / Eilat, Avital / Sternlicht, Keren / Benyamini, Lilach / Reish, Orit / Falik-Zaccai, Tzipora / Ben-Gad, Gali / Rod, Raya / Segel, Reeval / Kim, Katherine / Burton, Barabra / Keegan, Catherine E / Wagner, Mallory / Henderson, Lindsay B / Mor, Nofar / Barel, Ortal / Hirsch, Yoel /
    Meiner, Vardiella / Elpeleg, Orly / Harel, Tamar / Mor-Shakad, Hagar

    Journal of medical genetics

    2024  Volume 61, Issue 3, Page(s) 289–293

    Abstract: Background: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to ... ...

    Abstract Background: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.
    Methods: Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals.
    Results: We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in
    Conclusions: An Ashkenazi Jewish homozygous founder variant in
    MeSH term(s) Humans ; Intellectual Disability/genetics ; Jews/genetics ; Homozygote ; Syndrome ; Neurodevelopmental Disorders
    Language English
    Publishing date 2024-02-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg-2023-109504
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 177: Show issues Location:
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  3. Article ; Online: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.

    Ezer, Shlomit / Daana, Muhannad / Park, Julien H / Yanovsky-Dagan, Shira / Nordström, Ulrika / Basal, Adily / Edvardson, Simon / Saada, Ann / Otto, Markus / Meiner, Vardiella / Marklund, Stefan L / Andersen, Peter Munch / Harel, Tamar

    Brain : a journal of neurology

    2021  Volume 145, Issue 3, Page(s) 872–878

    Abstract: Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of- ... ...

    Abstract Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.
    MeSH term(s) Amyotrophic Lateral Sclerosis/metabolism ; DNA, Complementary ; Humans ; Infant ; Mutation/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics ; Syndrome ; Valine/genetics
    Chemical Substances DNA, Complementary ; SOD1 protein, human ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; Valine (HG18B9YRS7)
    Language English
    Publishing date 2021-11-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab416
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ui II Zs.26: Show issues Location:
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  4. Article ; Online: Spironolactone inhibits the growth of cancer stem cells by impairing DNA damage response.

    Gold, Ayala / Eini, Lital / Nissim-Rafinia, Malka / Viner, Ruth / Ezer, Shlomit / Erez, Keren / Aqaqe, Nasma / Hanania, Rotem / Milyavsky, Michael / Meshorer, Eran / Goldberg, Michal

    Oncogene

    2019  Volume 38, Issue 17, Page(s) 3103–3118

    Abstract: The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and ... ...

    Abstract The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and resistance to chemotherapy, raising the need for discovering drugs that target CSCs. Previously we have found that the antihypertensive drug spironolactone impairs DNA damage response in cancer cells. Here we show that spironolactone, apart from inhibiting cancerous cell growth, is also highly toxic to CSCs. Notably, we demonstrate that CSCs have high basal levels of DNA double-strand breaks (DSBs). Mechanistically, we reveal that spironolactone does not damage the DNA but impairs DSB repair and induces apoptosis in cancer cells and CSCs while sparing healthy cells. In vivo, spironolactone treatment reduced the size and CSC content of tumors. Overall, we suggest spironolactone as an anticancer reagent, toxic to both cancer cells and, particularly to, CSCs.
    MeSH term(s) Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/drug effects ; DNA Repair/drug effects ; Drug Repositioning ; HeLa Cells ; Humans ; Mice ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplastic Stem Cells/drug effects ; Spironolactone/administration & dosage ; Spironolactone/pharmacology ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Spironolactone (27O7W4T232)
    Language English
    Publishing date 2019-01-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-018-0654-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2218: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  5. Article ; Online: Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

    Yap, Zheng Yie / Park, Yo Han / Wortmann, Saskia B / Gunning, Adam C / Ezer, Shlomit / Lee, Sukyeong / Duraine, Lita / Wilichowski, Ekkehard / Wilson, Kate / Mayr, Johannes A / Wagner, Matias / Li, Hong / Kini, Usha / Black, Emily Davis / Monaghan, Kristin G / Lupski, James R / Ellard, Sian / Westphal, Dominik S / Harel, Tamar /
    Yoon, Wan Hee

    Genome medicine

    2021  Volume 13, Issue 1, Page(s) 55

    Abstract: Background: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. ... ...

    Abstract Background: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.
    Methods: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.
    Results: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.
    Conclusion: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.
    MeSH term(s) ATPases Associated with Diverse Cellular Activities/genetics ; Adolescent ; Alleles ; Amino Acid Sequence ; Animals ; Autophagy/genetics ; Computer Simulation ; Drosophila/ultrastructure ; Female ; Genetic Variation ; Humans ; Infant ; Infant, Newborn ; Locomotion ; Male ; Membrane Proteins/genetics ; Mitochondria/genetics ; Mitochondrial Proteins/genetics ; Mitophagy/genetics ; Mutation, Missense/genetics ; Neurogenesis/genetics ; Neurons/metabolism ; Pedigree ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Young Adult
    Chemical Substances ATAD3A protein, human ; Membrane Proteins ; Mitochondrial Proteins ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-)
    Language English
    Publishing date 2021-04-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2484394-5
    ISSN 1756-994X ; 1756-994X
    ISSN (online) 1756-994X
    ISSN 1756-994X
    DOI 10.1186/s13073-021-00873-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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